1. Field of the Invention
The present invention relates to a method producing 2-sulfonylpyridine derivatives. The 2-sulfonylpyridine derivatives produced by the present invention are useful as starting materials for synthesis of drugs, agricultural chemicals, etc., such as the synthesis starting materials of drug intermediates, including 5-aminomethyl-2-chloropyridine which is useful as an intermediate for synthesis of chloronicotinyl pesticides, 2,5-dichloropyridine which is an intermediate for synthesis of lazabemide, whose clinical development as an anti-Parkinson""s disease drug is being promoted, 2-hydroxypyridine, etc. (refer to U.S. Pat. No. 4,897,488, International Patent Application Laid-open No. W096/26188, International Patent Application Laid-open No. W098/11071, and Japanese Patent Application Laid-open No. 9-59254).
Moreover, the present invention relates to a method for producing 2-{[(2-pyridyl)methyl]thio}-1H-benzimidazole derivatives. The 2-{[(2-pyridyl)methyl]thio}-1H-benzimidazole derivatives obtained by the present invention are useful as, for instance, intermediates of 2-{[(2-pyridyl)methyl]sulfinyl}-1H-benzimidazole derivatives, compounds related to omeprazole, which is useful as an anti-ulcer agent.
2. Related Art of the Invention
Many physiologically active substances with a pyridine skeleton have been discovered in recent years. As methods for producing 2-sulfonylpyridine derivatives that are useful as intermediates for synthesis of these compounds, there are known, for example:
(1) The method in which sulfonyl cyanide is reacted with an acyloxybutadiene derivative (refer to International Patent Application Laid-open No. WO96/26188);
(2) The method in which p-toluenesulfonyl cyanide is reacted with 1-ethoxy-2-methylbutadiene (refer to Synthesis, p. 623 (1989) and International Patent Application Laid-Open No. WO98/11071);
(3) The synthesis method in which 2-halogenopyridine is reacted with an alkali metal thiolate to produce sulfenylpyridine, and then the sulfenylpyridine is gradually oxidized (refer to Journal of the Chemical Society Perkin Transaction 1, page 1839 (1984)).
However, the above-mentioned methods (1) and (2) have problems in that they have to use a diene compound that is thermally unstable, and the above-mentioned method (3) has problems in that there are many steps, the desired product yield is low, etc., and therefore, these methods can not be considered to be industrially efficient methods for producing 2-sulfonylpyridine derivatives.
In addition, the method in which a 2-halomethylpyridine derivative is reacted with a metal salt of a 2-mercapto-1H-benzimidazole derivative is known as a method for producing a 2-{[(2-pyridyl)methyl]thio}-1H-benzimidazole derivative, and when this is oxidized, a 2- {[(2-pyridyl)methyl]sulfinyl}-1H-benzimidazole derivative can be obtained (refer to U.S. Pat. No. 4,255,431). The 2-halomethylpyridine derivative that is used as the starting material for this method is produced via many steps using 2,3,5-trimethylpyridine as the starting material (refer to, for instance, U.S. Pat. No. 4,544,750 and Japanese Patent Application Laid-open No. 5-70434).
However, conventional methods for producing 2-{[(2-pyridyl)methyl]thio}-1H-benzimidazole derivatives can not be considered to be efficient production methods because many steps are needed to produce the starting 2-halomethylpyridine derivative. Moreover, there are problems in that 2-halomethylpyridine derivatives have poor shelf life and they must therefore be used in the next reaction immediately after synthesis.
The object of the present invention is to provide a method for producing 2-sulfonylpyridine derivatives industrially with efficiency in a good yield under moderate conditions.
Moreover, another object of the present invention is to provide a novel method for producing, efficiently synthesized in a short process, 2-{[(2-pyridyl)methyl]thio}-1H-benzimidazole derivatives, which are precursors of 2-{[(2-pyridyl)methyl]sulfinyl}-1H-benzimidazole derivatives.
The inventors have found that a 2-sulfonylpyridine derivative can be industrially produced efficiently by reacting a sulfonyl cyanide derivative with an xcex1,xcex2-unsaturated carbonyl compound and that a 2-{[(2-pyridyl)methyl]thio}-1H-benzimidazole skeleton can be formed in one step in a good yield.by reacting this type of 2-sulfonylpyridine derivative with a 2-methylthio-1H-benzimidazole derivative in the presence of an organolithium compound, and completed the present invention based on these findings.
That is, the present invention provides a method for producing a 2-sulfonylpyridine derivative represented by the formula (III) 
(In the formula, R1 is a hydrogen atom or an alkyl group or an aryl group that may be substituted, R2 and R3 are a hydrogen atom, a halogen atom, or an alkyl group or an aryl group that may be substituted, R4 is a hydrogen atom, a halogen atom, an alkoxyl group, an alkylthio group, a cyano group, an acyloxy group, an alkoxycarbonyl group, a protected amino group that may be substituted, or an alkyl group or an aryl group that may be substituted, and together R2 and R3 or R3 and R4 can represent xe2x80x94(CH2)nxe2x80x94(n is 3 or 4.), and R5 is an alkyl group, a cycloalkyl group, an aryl group or an aralkyl group that may be substituted.), which method comprises:
reacting an xcex1,xcex2-unsaturated carbonyl compound represented by general formula (I) 
(In the formula, R1, R2, R3 and R4 are the same as previously defined.) with a sulfonyl cyanide represented by general formula (II)
R5SO2CNxe2x80x83xe2x80x83(II)
(In the formula, R5 is the same as previously defined.) to obtain the 2-sulfonylpyridine derivative represented by general formula (III).
Moreover, the present invention provides a method for producing a 2-{[(4-alkoxy-2-pyridyl)methyl]thio}-1H-benzimidazole derivatives (VII) 
(In the formula, R1, R2 and R4 are the same as previously defined. X is a hydrogen atom, a halogen atom or an alkyl group, an alkenyl group, an aryl group, an aralkyl group or an alkoxyl group that may be substituted, and R6 is an alkyl group.), which method comprises:
reacting a halogeno-xcex1,xcex2-unsaturated carbonyl compound represented by general formula (I-1) 
xe2x80x83(In the formula, R1, R2 and R4 are the same as previously defined, and R31 is a halogen atom.) with a sulfonyl cyanide represented by general formula (II)
xe2x80x83R5SO2CNxe2x80x83xe2x80x83(II)
xe2x80x83(In the formula, R5 is the same as previously defined.) to obtain a 4-halogeno-2-sulfonylpyridine derivative represented by general formula (III-1) 
xe2x80x83(In the formula, R1, R2, R31, R4 and R5 are the same as previously defined.),
reacting the obtained derivative of general formula (III-1) in the presence of an organolithium compound with a 2-methylthio-1H-benzimidazole derivative represented by general formula (IV) 
xe2x80x83(In the formula, X is the same as previously defined.) to obtain a 2-{[(4-halogeno-2-pyridyl)methyl]thio}-1H-benzimidazole derivative represented by general formula (V) 
xe2x80x83(In the formula, R1,R2, R3, R4 and X are the same as previously defined.),
reacting the obtained derivative of general formula (V) with a metal alkoxide represented by general formula (VI)
R6OMxe2x80x83xe2x80x83(VI)
xe2x80x83(In the formula, R6 is the same as defined above, and M is an alkali metal or an alkaline earth metal.), to obtain the 2-{[(4-alkoxy-2-pyridyl)methyl]thio}-1H-benzimidazole derivative represented by general formula (VII).
In addition, the present invention provides a method for producing a 2-{[(4-halogeno-2-pyridyl)methyl]thio}-1H-benzimidazole derivative represented by general formula (V) 
(In the formula, R1, R2, R31, R4 and X are the same as previously defined.), which method comprises:
reacting, in the presence of an organolithium compound, a 4-halogeno-2-sulfonylpyridine derivative represented by general formula (III-1) 
xe2x80x83(In the formula, R1, R2, R31, R4 and R5 are the same as previously defined.), with a 2-methylthio-1H-benzimidazole derivative represented by general formula (IV) 
xe2x80x83(In the formula, X is the same as previously defined.), to obtain the derivative of general formula (V).
The present invention also provides a 4-chloro-3,5-dimethyl-2-sulfonylpyridine derivative represented by general formula (III-1a) 
(In the formula, R5 is the same as previously defined.).
The present invention further provides a method for producing a 2-{[(4-alkoxy-2-pyridyl)methyl]thio}-1H-benzimidazole derivative represented by general formula (VII) 
(In the formula, R1, R2, R4, R6 and X are the same as previously defined.), which method comprises:
reacting a 2-{[(4-halogeno-2-pyridyl)methyl]thio}-1H-benzimidazole derivative represented by general formula (V) 
xe2x80x83(In the formula, R1, R2, R31, R4 and X are the same as previously defined.), with a metal alkoxide represented by general formula (VI)
R6OMxe2x80x83xe2x80x83(VI)
xe2x80x83(In the formula, R6 and M are the same as previously defined.), to obtain the derivative of general formula (VII).
The present invention also provides a 2-{[(4-chloro-3,5-dimethyl-2-pyridyl)methyl]thio}-1H-benzimidazole derivative represented by general formula (V-1) 
(In the formula, X is the same as previously defined.).
Moreover, the present invention provides a method for producing a 2-{[(4-alkoxy-2-pyridyl)methyl]thio}-1H-benzimidazole derivative represented by general formula (VII) 
(In the formula, R1, R2, R4, R6 and X are the same as previously defined.), which method comprises:
reacting, in the presence of an organolithium compound, an 4-alkoxy-2-sulfonylpyridine derivative represented by general formula (VIII) 
xe2x80x83(In the formula, R1, R2, R4, R5 and R6 are the same as previously defined.), with a 2-methylthio-1H-benzimidazole derivative represented by general formula (IV) 
xe2x80x83(In the formula, X is the same as previously defined.), to obtain the derivative of general formula (VII).
The present invention also provides a 4-methoxy-3,5-dimethyl-2-sulfonylpyridine derivative represented by general formula (VIII-1) 
(In the formula, R5 is the same as previously defined.).
These and other objects, features and advantages of the present invention are described in or will become apparent from the following detailed description of the invention.
The present invention will be described in detail while referring to the following reaction scheme. 
First, the substitution groups in the general formulas shown in the above mentioned reaction scheme will be described.
Examples of the alkyl groups represented by each of R1, R2, R3, R4, R5 and X include linear or branched alkyl groups such as a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a tert-butyl group and a hexyl group. These alkyl groups may be substituted with ,e.g., halogen atoms such as a chlorine atom, a bromine atom, an iodine atom and a fluorine atom; alkoxyl groups such as a methoxy group, an ethoxy group, a propoxy group and a butoxy group; a hydroxyl group; tri-substituted silyloxy groups such as a tert-butyldimethylsilyloxy group and a tert-butyl diphenylsilyloxy group; a nitro group.
Examples of the aryl groups represented by each of R1, R2, R3, R4, R5 and X include a phenyl group, a naphthyl group, etc. These aryl groups may be substituted with, e.g., halogen atoms such as a chlorine atom, a bromine atom, an iodine atom and a fluorine atom; alkoxyl groups such as a methoxy group, an ethoxy group, a propoxy group and butoxy group; alkyl groups such as a methyl group, en ethyl group, a propyl group and butyl group; a hydroxyl group; tri-substituted silyloxy groups such as a tert-butyldimethylsilyloxy group and a tert-butyldiphenylsilyloxy group; a nitro group; and aryl groups such as a phenyl group and p-methoxyphenyl group.
Examples of the alkoxyl groups represented by R4 include a methoxy group, an ethoxy group, a propoxy group, a butoxy group and a phenoxy group. Examples of the alkylthio groups represented by R4 include a methylthio group, an ethylthio group, a propylthio group and a butylthio group. Examples of the acyloxy groups represented by R4 include aliphatic or aromatic acyloxy groups such as an acetoxy group, a propanoyloxy group, a butanoyloxy group, a pivaloyloxy group and a benzoyloxy group. Examples of the alkoxycarbonyl groups represented by R4 include a methoxycarbonyl group, en ethoxycarbonyl group and a n-butoxycarbonyl group. Examples of the protected amino groups represented by R4 include amino groups that are protected by protecting groups such as an acetyl group, a benzoyl group, a benzenesulfonyl group, and a tert-butoxycarbonyl group, and that may be substituted with, e.g., alkyl groups such as a methyl group, an ethyl group a propyl group, an isopropyl group, a butyl group, an isobutyl group and tert-butyl group.
Examples of the cycloalkyl groups represented by R5 include a cyclopropyl group, a cyclopentyl group and cyclohexyl group. These cycloalkyl groups may be substituted with, e.g., halogen atoms such as a chlorine atom, a bromine atom, an iodine atom and a fluorine atom; alkoxyl groups such as a methoxy group, an ethoxy group, a propoxy group and butoxy group; a hydroxyl group; tri-substituted silyloxy groups such as a tert-butyldimethylsilyloxy group and a tert-butyldiphenylsilyloxy group; a nitro group; and aryl groups such as a phenyl group and a p-methoxyphenyl group.
Examples of the aralkyl groups represented by R5 and X include a benzyl group and a phenethyl group. These aralkyl groups may be substituted with, e.g., halogen atoms such as a chlorine atom, a bromine atom, an iodine atom and a fluorine atom; alkoxyl groups such as a methoxy group, an ethoxy group, a propoxy group and a butoxy group; alkyl groups such as a methyl group, an ethyl group, a propyl group, an isopropyl group and a butyl group; a hydroxyl group; tri-substituted silyloxy groups such as a tert-butyldimethylsilyloxy group and a tert-butyldiphenylsilyloxy group; a nitro group; and aryl groups such as a phenyl group and a p-methoxyphenyl group.
Examples of the alkenyl groups represented by X include a vinyl group, a propenyl group, a methallyl group, a butenyl group, a prenyl group and an octenyl group. Examples of the alkoxyl groups represented by X include a methoxy group, an ethoxy group and an isopropoxyl group. These alkenyl groups and alkoxyl groups may be substituted with, e.g., halogen atoms such as a chlorine atom, a bromine atom, an iodine atom and a fluorine atom; alkoxyl groups such as a methoxy group, an ethoxy group, a propoxy group and a butoxy group; a hydroxyl group; tri-substituted silyloxy groups such as a tert-butyldimethylsilyloxy group and tert-butyldiphenylsilyloxy group; a nitro group; and aryl groups such as a phenyl group and a p-methoxyphenyl group.
Examples of the halogen atoms represented by each of X, R2, R3, R31 and R4 include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.
Examples of the alkyl groups represented by R6 include linear or branched alkyl groups such as a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a tert-butyl group and a hexyl group.
Examples of the alkali metal represented by M include lithium, sodium and potassium, and examples of the alkaline earth metal represented by M include magnesium and calcium.
Next, the present invention will be described in detail with each step:
Step (a)
The 2-sulfonylpyridine derivative (III) is obtained by reacting the sulfonyl cyanide (II) with the xcex1,xcex2-unsaturated carbonyl compound (I).
The reaction in this step (a) is usually performed in the presence of a solvent. There are no special restrictions to the solvent that is used as long as it will not have detrimental effects on the reaction. Examples of the solvents include aliphatic hydrocarbons such as pentane, hexane, heptane, octane and petroleum ether; aromatic hydrocarbons such as benzene, toluene, xylene and cumene; ethers such as diethyl ether, tetrahydrofuran, diisopropyl ether, dimethoxyethane and dibutyl ether; nitriles such as acetonitrile, propionitrile and benzonitrile; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane and trichloroethane; dimethyl sulfoxide; and mixtures thereof. The amount of solvent used is preferably within a range of 0.1 to 200 times part by weight relative to the sulfonyl cyanide (II).
The reaction is performed in the presence or absence of a catalyst, and an acid catalyst or an ammonium salt, etc., is used as the catalyst. Examples of acid catalysts include boric acid and esters thereof such as triethyl borate and tributyl borate; phosphoric acid and esters thereof such as tributyl phosphate; alkali metal salts of perchloric acid such as sodium perchlorate and lithium perchlorate; weakly acidic ion-exchange resins such as IRC-50 (Organo Co., Ltd.). Moreover, Examples of ammonium salts include ammonium chloride and benzyltrimethylammonium chloride. The amount of catalyst used is preferably within a range of 0.01 to 1 equivalent per the sulfonyl cyanide (II).
Moreover, the reaction can be performed in the presence of an alcohol. Examples of the alcohols include methanol, ethanol, isopropanol, butanol and isoamyl alcohol. The amount of alcohol used is preferably within a range of 0.1 to 200 equivalents per the sulfonyl cyanide (II).
The reaction is preferably performed while refluxing the mixed solution of a solvent, the xcex1,xcex2-unsaturated carbonyl compound (I) and the sulfonyl cyanide (II). There are no special restrictions to the amount of the sulfonyl cyanide (II) used per the xcex1,xcex2-unsaturated carbonyl compound (I), but it is preferred that the sulfonyl cyanide (II) can be used within a range of 0.5 mole to 1 mole per 1 mole of the xcex1,xcex2-unsaturated carbonyl compound (I). Moreover, the reaction temperature is preferably within a range of from 0xc2x0 C. to 200xc2x0 C., more preferably within a range of from 80xc2x0 C. to 120xc2x0 C.
The 2-sulfonylpyridine derivative (III) obtained in this way can be isolated and purified by methods normally used to isolate and purify organic compounds. For example, the derivative (III) can be recrystallized and thereby purified by concentrating and cooling the reaction mixture. Moreover, it is possible to concentrate the reaction mixture as is and then purify the crude product that is obtained by distillation, chromatography, etc., as necessary.
In addition, water is generated as the reaction proceeds, but the 2-sulfonylpyridine derivative (III) can be obtained in a high yield by performing the reaction while removing the water. There are no special restrictions to the method for removing the water, but the water can be efficiently removed by using a solvent that is an azeotrope with water and performing azeotropic distillation to outside the system using the solvent. Moreover, a dehydrator that will not have a detrimental effect on the reaction, such as molecular sieves, etc., can also be present within the system.
Furthermore, the xcex1,xcex2-unsaturated carbonyl compound (I) and the sulfonyl cyanide (II) used as the starting materials are both known compounds and can be easily acquired or produced. For instance, the xcex1,xcex2-unsaturated carbonyl compound (I) can be synthesized by aldol condensation (refer to, for instance, Japanese Patent Application Laid-open No.9-59201 and U.S. Pat. No. 4,873,362). Moreover, the sulfonyl cyanide (II) can be produced by reacting a corresponding sulfinic acid metal salt with halogenated cyanogen (refer to Organic Synthesis, volume 6, page 727 (1988)).
Step (axe2x80x2)
The sulfonyl cyanide (II) is reacted with the halogeno-xcex1,xcex2-unsaturated carbonyl compound (I-1) to obtain the 4-halogeno-2-sulfonylpyridine derivative (III-1), which is the starting material for producing the 2-{[(2-pyridyl)methyl]thio}-1H-benzimidazole skeleton. The 4-chloro-3,5-dimethyl-2-sulfonylpyridine derivative (III-1a), where R1 is a hydrogen atom, R2 and R4 are both methyl groups and R31 is a chlorine atom, is particularly preferred as the derivative (III-1).
Furthermore, this step (axe2x80x2) can be executed by conducting the same procedure as in step (a), with the exception that R3 of the xcex1,xcex2-unsaturated carbonyl compound (I) is limited to a halogen atom (R31).
Step (b)
The 2-methylthio-1H-benzimidazole derivative (IV) is reacted with the 4-halogeno-2-sulfonylpyridine derivative (III-1) in the presence of an organolithium compound to obtain the 2-{[(4-halogeno-2-pyridyl)methyl]thio}-1H-benzimidazole derivative (V).
The 2-{[(4-chloro-3,5-dimethyl-2-pyridyl)methyl]thio}-1H-benzimidazole derivative (V-1) is particularly preferred as the derivative (V) where R1 is a hydrogen atom, R2 and R4 are both methyl groups and R31 is a chlorine atom.
Examples of the organolithium compounds that is used include alkyllithium compounds such as methyllithium, n-butyllithium, sec-butyllithium, and tert-butyllithium; aryllithium compounds such as phenyllithium; alkenyllithium compounds such as vinyllithium; and lithium amide compounds such as lithium diisopropylamide, and lithium bis-trimethylsilylamide. Of these, alkyllithium compounds are preferably used. There are no restrictions in a strict sense to the amount of organolithium compound that is used, but it is preferred that the organolithium compound can be used within a range of 1 mole to 10 moles per 1 mole of the 2-methylthio-1H-benzimidazole derivative (IV), and from the point of smooth progression of the reaction, it is further preferred that the organolithium compound can be used within a range of 2 moles to 3 moles per 1 mole of the 2-methylthio-1H-benzimidazole derivative (IV).
The amount of the 4-halogeno-2-sulfonylpyridine derivative (III-1) used is preferably within a range of 1 mole to 10 moles, more preferably within a range of 1 mole to 2 moles, per 1 mole of the 2-methylthio-1H-benzimidazole derivative (IV).
The reaction is preferably performed in the presence of a solvent. There are no particular restrictions to the solvent that is used as long as it will not have a detrimental effect on the reaction, and examples of the solvents include aliphatic hydrocarbons such as pentane, hexane, heptane, octane and petroleum ether; aromatic hydrocarbons such as benzene, toluene, xylene and cumene; and ethers such as diethyl ether, tetrahydrofuran, diisopropyl ether, dimethoxy ethane and dibutyl ether. One of these solvents can be used alone, or 2 or more can be mixed and used together. The amount of solvent used is preferably within a range of 0.5 to 50 times part by weight, more preferably within a range of 3 to 20 times part by weight relative to the 2-methylthio-1H-benzimidazole derivative (IV).
Moreover, a tertiary amine compound, such as triethylamine, tributylamine, trioctylamine, N,N,Nxe2x80x2,Nxe2x80x2-tetramethylethylenediamine, 1,4-diazabicyclo[2.2.2]octane and 1,8-diazabicyclo[5.4.0]-7-undecene, etc., can be further added to the reaction system for the purpose of promoting the reaction under moderate conditions. Of these, 1,4-diazabicyclo[2.2.2]octane is preferred. There are no special restrictions to the amount used when a tertiary amine compound is added, but 1 mole or more per 1 mole of the organolithium compound is preferred, and within a range of 1 mole to 2 moles is further preferred, from the point of realizing the above mentioned purpose.
The reaction temperature can be selected as needed from within a range of from xe2x88x92100xc2x0 C. to the boiling point of the solvent that is used, and a range of from xe2x88x9250xc2x0 C. to 0xc2x0 C. is further preferred.
This reaction is performed, for instance, as follows: That is, the 2-methylthio-1H-benzimidazole derivative (IV) and a solvent are mixed and brought to a specific temperature, a solution of the organolithium compound is added dropwise to the mixture, next, the 4-halogeno-2-sulfonylpyridine derivative (III-1) dissolved in the solvent is added dropwise at a specific temperature, and then the reaction mixture is agitated at the same temperature until the 2-methylthio-1H-benzimidazole derivative (IV) disappears. It is preferred that when the tertiary amine compound is added, it be added before dropwise addition of the solution of the organolithium compound.
The 2-{[(4-halogeno-2-pyridyl)methyl]thio}-1H-benzimidazole derivative (V) that is obtained in this way can be isolated and purified by methods normally used to isolate and purify organic compounds. For example, the derivative (V) can be isolated and purified by adding water to the reaction solution, the organic layer is separated, the aqueous layer is extracted with an organic solvent, the extract and the organic layer are combined, dried and then concentrated to give the desired product and when necessary, the product is further purified by recrystallization, chromatography, etc. Moreover, this product can be used as is in step (c) described below without being purified.
Furthermore, the 2-methylthio-1H-benzimidazole derivative (IV) can be easily synthesized by reacting a phenylenediamine derivative represented by general formula (IX) 
(In the formula, X is the same as previously defined.) with carbon disulfide in the presence of zinc metal and an acid to obtain the 2-mercapto-1H-benzimidazole derivative (refer to, for instance, European Patent Application No. 609909A1), and then methylation of the 2-mercapto-1H-benzimidazole derivative.
Step (c)
The 2-{[(4-alkoxy-2-pyridyl)methyl]thio}-1H-benzimidazole derivative (VII) is obtained by reacting the 2-{[(4-halogeno-2-pyridyl)methyl]thio}-1H-benzimidazole derivative (V) and the metal alkoxide (VI).
Examples of the metal alkoxides (VI) include sodium methoxide, sodium ethoxide, potassium methoxide, lithium methoxide, sodium isopropoxide, potassium tert-butoxide, magnesium dimethoxide and calcium dimethoxide, and of these, sodium methoxide is particularly preferred. The amount of metal alkoxide (VI) used is preferably within a range of 0.1 mole to 10 moles, more preferably within a range of 1 mole to 2 moles per 1 mole of the 2-{[(4-halogeno-2-pyridyl)methyl]thio}-1H-benzimidazole derivative (V).
The reaction is preferably performed in the presence of a solvent. There are no particular restrictions to the solvent that is used as long as it will not have detrimental effects on the reaction. Examples of the solvents include alcohols such as methanol, ethanol, isopropyl alcohol and n-butanol; aliphatic hydrocarbons such as pentane, hexane, heptane, octane and petroleum ether; aromatic hydrocarbons such as benzene, toluene, xylene and cumene; ethers such as diethyl ether, tetrahydrofuran, diisopropyl ether, dimethoxy ethane and dibutyl ether; and aprotic solvents such as dimethylsulfoxide and N,N-dimethylformamide. One of these solvents can be used alone, or 2 or more can be used as a mixture. The amount of solvent is preferably within a range of 0.5 to 50 times, more preferably 3 to 10 times by weight relative to the 2-{[(4-halogeno-2-pyridyl)methyl]thio}-1H-benzimidazole derivative (V).
The reaction temperature can be selected as needed from within a range of from 20xc2x0 C. to the boiling point of the solvent that is used, and a range of from 30xc2x0 C. to 100xc2x0 C. is further preferred.
This reaction is, for instance, performed as described below: That is, specific amounts of the 2-{[(4-halogeno-2-pyridyl)methyl]thio}-1H-benzimidazole derivative (V), the metal alkoxide (VI) and a solvent are mixed and agitated at a specific temperature until the 2-{[(4-halogeno-2-pyridyl)methyl]thio}-1H-benzimidazole derivative (V) disappears.
The 2-{[(4-alkoxy-2-pyridyl)methyl]thio}-1H-benzimidazole derivative (VII) thus obtained can be isolated and purified by methods normally used to isolate and purify organic compounds. For instance, water is added to the reaction solution and the organic layer is separated, the aqueous layer is extracted with organic solvent, the extract and the organic layer are combined, dried and then concentrated to give the desired, crude product, and when necessary, the crude product is further purified by recrystallization, chromatography, etc.
Step (d)
The 2-methylthio-1H-benzimidazole derivative (IV) is reacted with the 4-alkoxy-2-sulfonylpyridine derivative (VIII) in the presence of an organolithium compound to obtain the 2-{[(4-alkoxy-2-pyridyl)methyl]thio}-1H-benzimidazole derivative (VII).
This step (d) can be performed by conducting the same procedure as in step (b), with the exception that the 4-alkoxy-2-sulfonylpyridine derivative (VIII), which is a compound where R31 of the 4-halogeno-2-sulfonylpyridine derivative (III-1) is substituted with alkoxyl groups (xe2x80x94OR6), is used. Here, the 4-methoxy-3,5-dimethyl-2-sulfonylpyridine derivative (VIII-1) is particularly preferred as the derivative (VIII) where R1 is a hydrogen atom and R2, R4 and R6 are all methyl groups.
The 2-{[(4-alkoxy-2-pyridyl)methyl]thio}-1H-benzimidazole derivative (VII) obtained in this way can be easily converted to the 2-{[(4-alkoxy-2-pyridyl)methyl]sulfinyl)-1H-benzimidazole derivative, typically, omeprazole (2-{2-[(3,5-dimethyl-4-methoxypyridyl)methyl]sulfinyl}-(5-methoxy)-1H-benzimidazole), by an oxidation reaction.